The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins

Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, Barnett J, Leslie NR, Cheng S, Shepherd PR, Gout I, …, Lamb RF · 2004 · The Journal of Cell Biology · Atlas ID HAR2004

What this study shows

One of two 2004 papers that placed mTORC1's main negative feedback loop downstream of TSC-Rheb-S6K1 (rapamycin-sensitive IRS-1 degradation had been reported earlier, Haruta 2000). When mTORC1/S6K1 activity is left switched on, S6K1 phosphorylates IRS-1 and represses its expression, so the insulin receptor can no longer signal to PI3K. This is the textbook explanation for why blocking mTORC1 paradoxically raises Akt activity, and it contributes to insulin resistance when mTORC1 is chronically overactive (for example with TSC loss or nutrient excess). The insulin resistance seen with chronic rapamycin is instead attributed mainly to mTORC2 disruption (LAM2012).

Abstract

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Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1.

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At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Mammalian cells (TSC1/TSC2-null MEFs, human cells)) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Mammalian cells (TSC1/TSC2-null MEFs, human cells)
Journal	The Journal of Cell Biology
Year	2004
Peer reviewed	Yes
Record last updated	2026-07-29
Source	DOI 10.1083/jcb.200403069 · PMID 15249583

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Genetic loss of TSC1/TSC2; S6K1 activity manipulation
Target	S6K1 -> IRS-1 -> PI3K/Akt
Model	Mammalian cells
Effect	Sustained S6K1 activity depletes IRS-1 and uncouples the insulin receptor from PI3K

In the Atlas

Links in the pathway map

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Cite this paper

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Harrington, L. S., Findlay, G. M., Gray, A., Tolkacheva, T., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N. R., Cheng, S., Shepherd, P. R., Gout, I., Downes, C. P., & Lamb, R. F. (2004). The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. The Journal of Cell Biology. https://doi.org/10.1083/jcb.200403069

@article{HAR2004,
  author       = {Harrington, L. S. and Findlay, G. M. and Gray, A. and Tolkacheva, T. and Wigfield, S. and Rebholz, H. and Barnett, J. and Leslie, N. R. and Cheng, S. and Shepherd, P. R. and Gout, I. and Downes, C. P. and Lamb, R. F.},
  title        = {{The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins}},
  journal      = {The Journal of Cell Biology},
  year         = {2004},
  doi          = {10.1083/jcb.200403069},
  note         = {PMID: 15249583},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record HAR2004) [Data set]. https://mtor-atlas.org/study/HAR2004/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_HAR2004,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record HAR2004},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/HAR2004/},
  doi          = {10.5281/zenodo.22059963}
}

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